P1346: THE IMPACT OF CYTOTOXIC THERAPY ON THE RISK OF PROGRESSION AND DEATH IN PATIENTS WITH CLONAL CYTOPENIA OF UNDETERMINED SIGNIFICANCE.
Authors: LI Marissa, Anmol Baranwal, Syed Shah, Mark Gurney, Al-Kali Aref, Alkhateeb Hassan, Foran James, Cecilia Arana Yi, Dong Chen, Abhishek Mangaonkar, Kristen Mccoullough, Ayalew Tefferi, Mrinal Patnaik, Mithun Shah
Journal: HemaSphere (2023)

Topic: 23. Hematopoiesis, stem cells and microenvironment Background: Therapy-related myeloid neoplasm (t-MN) is a type of aggressive leukemia that develop as a complication of prior exposure to DNA-damaging agents. With advancing sequencing technology in the past decade, precursor states for myeloid neoplasm have been more commonly identified. Clonal cytopenia of undetermined significance (CCUS) is defined as the presence of cytopenia and evidence of clonality, in the absence of a diagnosis of myeloid neoplasm. Recent studies (Shah et al., 2022) demonstrate that therapy-related CCUS (t-CCUS) are a distinct clinical entity, conferring better median survival compared to t-MN. Aims: To assess the impact of prior cytotoxic therapy on the risk of progression to a myeloid neoplasm or death. Methods: This study is a retrospective review of all adult patients diagnosed with CCUS at Mayo Clinic. All patients who had MDS defining cytogenetics at diagnosis were excluded. Patients were designated as t-CCUS based on exposure to prior DNA-damaging agent(s). Demographic and clinical information was extracted at the time of diagnosis, including age, sex, blood count, therapy received following CCUS diagnosis, and NGS. Statistical analysis was performed using Stata. Survival outcomes were calculated using Cox-proportional hazard and logistic regression. Progression free- (PFS) was defined as the interval from the diagnosis to progression or death. Overall survival (OS) was defined as the interval from the diagnosis to death from any cause. Results: Of 151 patients identified, 105 (70%) had CCUS and 46 (30%) had t-CCUS. The median age at diagnosis for the entire cohort was 68 years and 60% were males. There were no differences between median blood counts at diagnosis between the two groups (median HGB 10.9, WBC 3.5, ANC 1.6, PLT 114). More CCUS patients had hypercellular bone marrow at diagnosis (45% vs. 17%, p=0.002), and more t-CCUS had hypocellular bone marrow at diagnosis (20% vs. 5%, p=0.011). There were no significant differences in the number of mutations on NGS or percentage of bone marrow blasts. The most common mutations in all comers were TET2, SRSF2, ASXL1, DNMT3A, ZRSR2, and U2AF1. CCUS was more enriched in SRSF2 mutations (29% vs 9%, p=0.006), whereas t-CCUS was disproportionally enriched in TP53 mutations (20% vs 2%, p=0.001, Figure A). There were no differences in median VAF (39% vs. 38.5% in CCUS and t-CCUS). A majority in both groups underwent surveillance only (71% vs. 80% in CCUS and t-CCUS), with the second most common method of treatment being supportive care (growth factor and/or transfusion, 15% vs 6%). After a median follow up of 2.5 years, CCUS had significantly longer PFS compared to t-CCUS, remaining consistent when adjusted for age and sex (6.3 years vs. 1.8 years, HR 2.1, p=0.007, Figure B). Similarly, median OS adjusted for age and sex was longer for CCUS compared to t-CCUS (NR vs. 3.6 years, HR 2.3, p=0.007, Figure C). MDS was the most common diagnosis upon progression in both cohorts (7.6% vs. 15% in CCUS and t-CCUS). The cause of death in the CCUS cohort was evenly distributed between all causes (23% disease/neoplasm related, 15% cardiac related, 30% infection related, 30% other/multifactorial). In contrast, the cause of death in t-CCUS cohort was 44% disease related, 22% cardiac, 11% infection 22% other/multifactorial (p=0.299). Summary/Conclusion: t-CCUS had distinct morphological and genetic features compared to CCUS and had a higher risk of progression to myeloid neoplasm and death. The t-CCUS group was also more likely to die from a direct disease related cause.Keywords: Therapy-related AML, Myeloid malignancies, CCUS